Endothelin (ET) receptor blockade delays the progression of
diabetic nephropathy; however, the mechanism of this protection is unknown. Therefore, the aim of this study was to test the hypothesis that ET(A) receptor blockade attenuates
superoxide production and
inflammation in the kidney of diabetic rats. Diabetes was induced by
streptozotocin (diabetic rats with partial
insulin replacement to maintain modest
hyperglycemia [HG]), and
sham rats received vehicle treatments. Some rats also received the ETA antagonist
ABT-627 (sham+ABT and HG+ABT; 5 mg/kg per d; n = 8 to 10/group). During the 10-wk study, urinary microalbumin was increased in HG rats, and this effect was prevented by ET(A) receptor blockade. Indices of oxidative stress, urinary excretion of
thiobarbituric acid reactive substances, 8-hydroxy--deoxyguanosine, and H2O2 and plasma
thiobarbituric acid reactive substances were significantly greater in HG rats than in
sham rats. These effects were not prevented by
ABT-627. In addition, renal cortical expression of 8-hydroxy--deoxyguanosine and
NADPH oxidase subunits was not different between HG and HG+ABT rats. ETA receptor blockade attenuated increases in macrophage infiltration and urinary excretion of
TGF-beta and
prostaglandin E2 metabolites in HG rats. Although
ABT-627 did not alleviate oxidative stress in HG rats,
inflammation and production of inflammatory mediators were reduced in association with prevention of microalbuminuria. These observations indicate that ETA receptor activation mediates renal
inflammation and
TGF-beta production in diabetes and are consistent with the postulate that ETA blockade slows progression of
diabetic nephropathy via an anti-inflammatory mechanism.